We have developed a rhesus monkey model to study the ontogeny of the midbrain-rostral forebrain dopamine circuitry, and have used this model to study the consequences of gestational cocaine exposure. Fetuses from these pregnancies develop a repertoire of neural deficiencies including decreased mRNA expression of tyrosine hydroxylase in the midbrain and increased mRNA expression and binding densities of dopamine receptor subtypes in the rostral forebrain. In addition, maternal exposure to cocaine increases gene expression of dynorphin and enkephalin in presumed dopamine target neurons in the rostral forebrain at both day 60 and day 70 of gestation. Enkephalin acts at mu-opioid receptors and these receptors are highly expressed in the fetal monkey brain. Moreover, gestational cocaine exposure decreased the mRNA concentration of mu receptors in the day 70 diencephalon. We have found previously that dopamine transporter (DAT) mRNA is present in low quantities in the midbrain of day 45 fetuses. By day 60 of gestation, the concentration of DAT mRNA in the midbrain is highly increased. Our hypothesis is that cocaine causes the developmental changes in the midbrain-rostral forebrain dopamine neurocircuitry through binding to the developing DAT, and thereby altering normal functioning of this system. To test this hypothesis, we measured the distribution of DAT binding sites and quantified the effects of cocaine treatment from day 22 to day 70 of gestation. We found that [125I]-RTI-121 binding to the DAT were highest in the substantia nigra and the ventral tegmental area (VTA), and cocaine treatment significantly increased the ligand binding sites in the VTA. The aim of current studies are to examine the more long-term effects of prenatal cocaine exposure and to assess the mechanisms involved in long-term changes of the midbrain-rostral forebrain dopaminergic neurocircuitry. The results from these studies will provide important information about normal development of the primate central nervous system and help increase our understanding of the consequences of in utero cocaine exposure.